Annuaire
2019
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Staphylococcus aureus Small Colony Variants (SCVs): News From a Chronic Prosthetic Joint Infection.
- Journal : Front Cell Infect Microbiol
- 2019
- Small colony variants (SCV) of Staphylococcus aureus have been reported as implicated in chronic infections. Here, we investigated the genomic and transcriptomic changes involved in the evolution from a wild-type to a SCV from in a patient with prosthetic joint infection relapse. The SCV presented a stablephenotype with no classical auxotrophy and the emergence of rifampicin resistance. Whole Genome Sequencing (WGS) analysis showed only the loss of a 42.5 kb phage and 3 deletions, among which one targeting the rpoB gene, known to be the target of rifampicin and to be associated to SCV formation in the context ofa constitutively active stringent response. Transcriptomic analysis highlighted a specific signature in the SCV strain including a complex, multi-level strategy of survival and adaptation to chronicity within the host including a protection from the inflammatory response, an evasion of the immune response, a constitutively activated stringent response and a scavenging of iron sources.
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Structural analysis reveals a "molecular calipers" mechanism for a LATERAL ORGAN BOUNDARIES DOMAIN transcription factor protein from wheat.
- Journal : J Biol Chem
- 2019
- LATERAL ORGAN BOUNDARIES DOMAIN (LBD) proteins, a family of plant-specific transcription factors harboring a conserved Lateral Organ Boundaries (LOB) domain, are regulators of plant organ development. Recent studies have unraveledadditional pivotal roles of the LBD protein family beyond defining lateral organboundaries, such as pollen development and nitrogen metabolism. The structural basis for the molecular network of LBD-dependent processes remains to be deciphered. Here, we solved the first structure of the homodimeric LOB domain ofRamosa2 from wheat (TtRa2LD) to 1.9 A resolution. Our crystal structure reveals structural features shared with other zinc-finger transcriptional factors, as well as some features unique to LBD proteins. Formation of the TtRa2LD homodimerrelied on hydrophobic interactions of its coiled-coil motifs. Several specific motifs/domains of the LBD protein were also involved in maintaining its overall conformation. The intricate assembly within and between the monomers determined the precise spatial configuration of the two zinc fingers that recognize palindromic DNA sequences. Biochemical, molecular modeling, and small-angle X-ray scattering experiments indicated that dimerization is important for cooperative DNA binding and discrimination of palindromic DNA through a molecular calipers mechanism. Along with previously published data, this study enables us to establish an atomic-scale mechanistic model for LBD proteins as transcriptional regulators in plants.
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System-wide Profiling of RNA-Binding Proteins Uncovers Key Regulators of Virus Infection.
- Journal : Mol Cell
- 2019
- The compendium of RNA-binding proteins (RBPs) has been greatly expanded by the development of RNA-interactome capture (RIC). However, it remained unknown if the complement of RBPs changes in response to environmental perturbations and whether these rearrangements are important. To answer these questions, we developed "comparative RIC" and applied it to cells challenged with an RNA virus called sindbis (SINV). Over 200 RBPs display differential interaction with RNA upon SINV infection. These alterations are mainly driven by the loss of cellular mRNAs andthe emergence of viral RNA. RBPs stimulated by the infection redistribute to viral replication factories and regulate the capacity of the virus to infect. For example, ablation of XRN1 causes cells to be refractory to SINV, while GEMIN5 moonlights as a regulator of SINV gene expression. In summary, RNA availability controls RBP localization and function in SINV-infected cells.
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TCTP and CSN4 control cell cycle progression and development by regulating CULLIN1 neddylation in plants and animals.
- Journal : PLoS Genet
- 2019
- Translationally Controlled Tumor Protein (TCTP) controls growth by regulating theG1/S transition during cell cycle progression. Our genetic interaction studies showthat TCTP fulfills this role by interacting with CSN4, a subunit of the COP9Signalosome complex, known to influence CULLIN-RING ubiquitin ligases activity bycontrolling CULLIN (CUL) neddylation status. In agreement with these data,downregulation of CSN4 in Arabidopsis and in tobacco cells leads to delayed G1/Stransition comparable to that observed when TCTP is downregulated. Loss-of-functionof AtTCTP leads to increased fraction of deneddylated CUL1, suggesting that AtTCTPinterferes negatively with COP9 function. Similar defects in cell proliferation andCUL1 neddylation status were observed in Drosophila knockdown for dCSN4 or dTCTP,respectively, demonstrating a conserved mechanism between plants and animals.Together, our data show that CSN4 is the missing factor linking TCTP to the controlof cell cycle progression and cell proliferation during organ development and openperspectives towards understanding TCTP's role in organ development and disordersassociated with TCTP miss-expression.
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The extruded non-template strand determines the architecture of R-loops.
- Journal : Nucleic Acids Res
- 2019
- Three-stranded R-loop structures have been associated with genomic instability phenotypes. What underlies their wide-ranging effects on genome stability remains poorly understood. Here we combined biochemical and atomic force microscopy approaches with single molecule R-loop footprinting to demonstrate that R-loops formed at the model Airn locus in vitro adopt a defined set of three-dimensionalconformations characterized by distinct shapes and volumes, which we call R-loopobjects. Interestingly, we show that these R-loop objects impose specific physical constraints on the DNA, as revealed by the presence of stereotypical angles in the surrounding DNA. Biochemical probing and mutagenesis experiments revealed that the formation of R-loop objects at Airn is dictated by the extruded non-template strand, suggesting that R-loops possess intrinsic sequence-driven properties. Consistent with this, we show that R-loops formed at the fission yeast gene sum3 do not form detectable R-loop objects. Our results reveal that R-loops differ by their architectures and that the organization of the non-template strand is a fundamental characteristic of R-loops, which could explain that only a subset of R-loops is associated with replication-dependent DNA breaks.
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The long noncoding RNA CHROME regulates cholesterol homeostasis in primate.
- Journal : Nat Metab
- 2019
- The human genome encodes thousands of long non-coding RNAs (lncRNAs), the majority of which are poorly conserved and uncharacterized. Here we identify a primate-specific lncRNA (CHROME), elevated in the plasma and atherosclerotic plaques of individuals with coronary artery disease, that regulates cellular andsystemic cholesterol homeostasis. LncRNA CHROME expression is influenced by dietary and cellular cholesterol via the sterol-activated liver X receptor transcription factors, which control genes mediating responses to cholesterol overload. Using gain- and loss-of-function approaches, we show that CHROME promotes cholesterol efflux and HDL biogenesis by curbing the actions of a set of functionally related microRNAs that repress genes in those pathways. CHROME knockdown in human hepatocytes and macrophages increases levels of miR-27b, miR-33a, miR-33b and miR-128, thereby reducing expression of their overlapping target gene networks and associated biologic functions. In particular, cells lacking CHROME show reduced expression of ABCA1, which regulates cholesterol efflux and nascent HDL particle formation. Collectively, our findings identify CHROME as a central component of the non-coding RNA circuitry controlling cholesterol homeostasis in humans.
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WASABI: a dynamic iterative framework for gene regulatory network inference
- Journal : BMC Bioinformatics
- 2019
Link to PubMed entry